Having focused on a specific type of ACAT that is present in the vascular wall, the present inventors previously studied a substance which selectively inhibits the ACAT, and found that, among azole compounds having a cyclic diamine structure, cyclic diamine derivatives represented by the following formula (3):
(wherein Ar represents a phenyl group, a pyridyl group, or a pyrimidinyl group which may have a substituent; X represents NH, S, or O; and ring A represents a benzene ring or a pyridine ring which may have a substituent; 1 is an integer of 1 or 2; m is an integer of 1 or 2; and n is an integer of 1 to 6) and salts thereof are useful therapeutic drugs for hyperlipidemia and arteriosclerosis by virtue of less side effect, excellent water-solubility, and peroral absorbability. They filed an international patent application on the basis of these findings (Patent Document 1).
The above patent application discloses a method for producing azole compounds (3′) including the cyclic diamine derivatives represented by the above formula (3). According to the method, as shown in the following reaction scheme:
(wherein Ar′ represents an aryl group which may have a substituent; X represents NH, S, or O; ring A′ represents a benzene ring, a pyridine ring, or a similar ring, any of which may have a substituent; Y represents S, O, or a similar element; e is an integer of 1 to 15; f is an integer of 1 or 2; and g is an integer of 1 to 3), a 1-(hydroxyalkyl)piperazine (a) is reacted with a haloalkylamide compound (b), to thereby produce an alcohol derivative (c). The hydroxyl group of the alcohol derivative is transformed into a leaving group such as a methanesulfonyloxy group, to thereby yield a compound (d), followed by reacting with a compound (e), to thereby produce an azole compound (3′).
However, the above method has drawbacks. For example, formation of the thioether bond during transformation of the alcohol derivative (c) to the cyclic diamine derivative (3′) requires two steps; i.e., methanesulfonylation and condensation with a compound (e). Since the methanesulfonyloxy species (d) formed in the first step is highly reactive, the final product yield decreases due to by-products formed during posttreatment after the first step or condensation with the compound (e).
Patent Document 1: Pamphlet of International Publication WO 98/54153